Expression of erythropoietin receptor in select non-hematopoietic tissue provides for erythropoietin response beyond erythroid progenitor cell survival, proliferation and differentiation. We previously observed erythropoietin receptor expression on myoblasts provides for erythropoietin response affecting the skeletal myogenic regulatory factor program including expression of GATA-4 and Tal1 mediated via Sirt1 and changes in the NAD+/NADH ratio. Examination of mitochondrial activity in skeletal muscle with mouse models that lack erythropoietin receptor in myoblasts or that express high level of transgenic erythropoietin reveals that erythropoietin influences oxidative activity and increases the proportion of slow twitch myofibers and levels of PGC-1alpha. In vitro studies of primary myoblast cultures show erythropoietin increases mitochondrial biogenesis gene expression, oxygen consumption rate and AMPK, which induces PGC-1alpha and slow oxidative fiber formation. These data suggest the potential for erythropoietin involvement in muscle fiber programming and metabolism during skeletal muscle development.